CXCL10 triggers early microglial activation in the cuprizone model.
A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.


Dynamic changes of functional segregation and integration in vulnerability and resilience to schizophrenia.
Schizophrenia (SZ) is a highly heritable disease with neurodevelopmental origins and significant functional brain network dysfunction. Functional network is heavily influenced by neurodevelopment processes and can be characterized by the degree of segregation and integration. This study examines functional segregation and integration in SZ and their first-degree relatives (high risk [HR]) to better understand the dynamic changes in vulnerability and resiliency, and disease markers. Resting-state functional magnetic resonance imaging data acquired from 137 SZ, 89 HR, and 210 healthy controls (HCs). Small-worldness σ was computed at voxel level to quantify balance between segregation and integration. Interregional functional associations were examined based on Euclidean distance between regions and reflect degree of segregation and integration. Distance strength maps were used to localize regions of altered distance-based functional connectivity. σ was significantly decreased in SZ compared to HC, with no differences in high risk (HR). In three-group comparison, significant differences were noted in short-range connectivity (primarily in the primary sensory, motor and their association cortices, and the thalamus) and medium/long-range connectivity (in the prefrontal cortices [PFCs]). Decreased short- and increased medium/long-range connectivity was found in SZ. Decreased short-range connectivity was seen in SZ and HR, while HR had decreased medium/long-range connectivity. We observed disrupted balance between segregation and integration in SZ, whereas relatively preserved in HR. Similarities and differences between SZ and HR, specific changes of SZ were found. These might reflect dynamic changes of segregation in primary cortices and integration in PFCs in vulnerability and resilience, and disease markers in SZ.


Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice.
The methylenetetrahydrofolate reductase (Mthfr) gene and/or abnormal homocysteine-folate metabolism are associated with increased risk for birth defects and neuropsychiatric diseases. In addition, disturbances of the GABAergic system in the brain as well as Mthfr polymorphism are associated with neurodevelopmental disorders such as schizophrenia and autism. In the present study we performed behavioral phenotyping of male and female Mthfr mice (wild type and their heterozygous littermates). The present study addresses two main questions: (1) genetic susceptibility, as examined by effects of Mthfr deficiency on behavior (Experiment 1) and (2) possible gene-drug interactions as expressed by behavioral phenotyping of Mthfr-deficient mice neonatally exposed to the GABA potentiating drug GVG (Experiment 2). Newborn development was slightly influenced by Mthfr genotype per se (Experiment 1); however the gene-drug interaction similarly affected reflex development in both male and female offspring (Experiment 2). Hyperactivity was demonstrated in Mthfr heterozygous male mice (Experiment 1) and due to GVG treatment in both Wt and Mthfr+/- male and female mice (Experiment 2). The gene-environment interaction did not affect anxiety-related behavior of male mice (Experiment 2). In female mice, gene-treatment interactions abolished the reduced anxiety observed due to GVG treatment and Mthfr genotype (Experiment 2). Finally, recognition memory of adult mice was impaired due to genotype, treatment and the gene-treatment combination in a sex-independent manner (Experiment 2). Overall, Mthfr deficiency and/or GABA potentiation differentially affect a spectrum of behaviors in male and female mice. This study is the first to describe behavioral phenotypes due to Mthfr genotype, GVG treatment and the interaction between these two factors. The behavioral outcomes suggest that Mthfr deficiency modulates the effects of GABA potentiating drugs. These findings suggest that future treatment strategies should consider a combination of genotyping with drug regimens.


The treatment and functional outcome of type IV coronal shear fractures of the distal humerus: a retrospective review of five cases.
To present the treatment method and outcome of 5 cases of type IV coronal shear fractures of the distal end of the humerus. Retrospective study. Five patients with an isolated type IV coronal shear fracture of the distal end of the humerus. Open reduction and internal fixation of the fractures utilizing Herbert screws, through a modified extensile lateral Kocher approach. Functional elbow index rating scale of Broberg-Morrey, Mayo Elbow Performance Score, subjective satisfaction rate and subjective functional limitations, and radiographic evaluation of the operated elbows for the presence or absence of osteonecrosis and degenerative joint disease changes. The follow-up time ranged from 39 to 50 months. All fractures healed within 6 to 9 weeks. The latest radiographic evaluation revealed mild degenerative joint disease changes in 1 patient and osteonecrosis of the coronal shear fragment in another. None of the patients reported pain even during strenuous activities, and none had clinical findings or subjective complaints suggesting instability of the elbow joint. Four patients regained full range of elbow motion compared with the contralateral elbow, and only 1 had a 10 degrees extension lag. The muscle strength of the major muscle groups of the operated elbow was equal to that of the uninjured elbow when tested clinically. No patient reported limitations in activities, and all indicated complete satisfaction with their outcome. According to the Broberg-Morrey scale and the Mayo Elbow Performance Score, all results were excellent, with scores ranging from 98 to 100 points. Recognition of this particular type of injury, prompt treatment with anatomic reduction and internal fixation, and early rehabilitation can lead to excellent functional outcomes.


The influence of severity of angulatory deformity of rat's tibia on spontaneous correction.
In order to estimate the spontaneous correctability of tibial deformity, retrocurvature of various degrees in the growing rat tibia was observed roentgenologically at 2 to 3 weekly intervals for eight week periods. The results obtained were: in the retrocurvated rat tibia of groups I, II and III, 11.1 +/- 2.6%, 7.2 +/- 1.7% and 7.4 +/- 1.1% respectively of initial base angle were corrected in observation periods of between 3 to 8 weeks and the correction obtained between 3 to 5 weeks in groups I, II and III were 4.2 +/- 1.3 degrees (65.5%), 4.3 +/- 1.5 degrees (64.2%) and 5.0 +/- 1.3 degrees (67.9%), and between 5 to 8 weeks were 2.2 +/- 0.6 degrees (34.4%), 2.4 +/- 0.5 degrees (35.8%) and 2.7 +/- 0.9 degrees (32.1%), respectively. This study confirms that spontaneous correctability of deformed rat tibia decreased when the deformity is severe, and, irrespective of the severity of initial deformity, more than half of the initial base angles were corrected in an early phase, and remainders later. This fact indicates that the physeal and diaphyseal remodelling process is affected to some degree by the severity of the deformity.


Performance Analysis of Anaplasma Antibody Competitive ELISA Using the ROC Curve for Screening of Anaplasmosis in Camel Populations in Egypt.
Anaplasmosis is a tick-born and potential zoonotic disease caused by Anaplasma (A.) phagocytophilum, A. ovis, A. platys and A. capra. Anaplasma marginale affecting bovines and camels causing significant economic losses. Camels as an integral part of the socio-economic lifestyle of nomads in semi-arid to arid ecosystems are prone to suffer from subclinical Anaplasma infections. This study aimed to determine the performance and adaptation of commercial competitive Anaplasma ELISA (cELISA) as a tool for screening the seroprevalence of anaplasmosis whitin the camel populations in Egypt. This study was based on the serological investigation of 437 camel sera collected between 2015 and 2016 during a Q fever prevalence study in Egypt using commercially available cELISA for the detection of antibodies specific for Anaplasma in bovine serum. The receiver operating characteristic (ROC) curve, an analysis method for optimizing cutoff values in cELISAs, was used to estimate the sensitivity and specificity using 76 true as serological positive (n = 7) and negative (n = 60) for Anaplasma antibodies. ROC curve analysis was done for 7 true positive and 60 true negative bovine samples and 7 true positive and 29 true negative camel samples serum. Real time PCR and/or conventional PCR was applied to confirm Anaplasma spp. specific-DNA in camel serum as an indication of a true positive and true negative for ROC analysis. Chi square analysis was performed to estimate the association between risk factors and anaplasmosis in camels. The cutoff value was determined as 0.42 (p value ≤ 0.001). Data simulation with randomly generated values revealed a cutoff value of 0.417 (p ≤ 0.001) with resulting 58.1% Se and 97.8% Sp. Seven true positive and 29 true negative camel serum samples was confirmed by PCR. Using the estimated cut off, the seroprevalence in the Nile Valley and Delta and the Eastern Desert domain was 47.4% and 46.4%, respectively. The potential risk factors as domains and origin of animals were less significantly associated with the prevalence of anaplasmosis (domains: χ(2) = 41.8, p value ≤ 0.001 and origin: χ(2) = 42.56, p value ≤ 0.001). Raising awareness especially for veterinarians and animal owners will significantly contribute to the best understanding of anaplasmosis in camels in Egypt. Alternative (in silico) validation techniques and preliminary prevalence studies are mandatory towards the control of neglected anaplasmosis in the camel population.


Techniques used to identify the Brazilian variant of HIV-1 subtype B.
The purpose of the present study was to compare the sensitivity and specificity of V3 enzyme immunoassay (solid phase EIA and EIA inhibition) and restriction fragment length polymorphism (RFLP) with the DNA sequencing "gold standard" to identify the Brazilian HIV-1 variants of subtype B and B"-GWGR. Peripheral blood mononuclear cells were collected from 61 HIV-1-infected individuals attending a clinic in São Paulo. Proviral DNA was amplified and sequentially cleaved with the Fok I restriction enzyme. Plasma samples were submitted to a V3-loop biotinylated synthetic peptide EIA. Direct partial DNA sequencing of the env gene was performed on all samples. Based on EIA results, the sensitivity for detecting B-GPGR was 70%, compared to 64% for the Brazilian variant B"-GWGR while, the specificity of B-GPGR detection was 85%, compared to 88% for GWGR. The assessment of RFLP revealed 68% sensitivity and 94% specificity for the B-GPGR strain compared to 84 and 90% for the B"-GWGR variant. Moreover, direct DNA sequencing was able to detect different base sequences corresponding to amino acid sequences at the tip of the V3 loop in 22 patients. These results show a similar performance of V3 serology and RLFP in identifying the Brazilian variant GWGR. However, V3 peptide serology may give indeterminate results. Therefore, we suggest that V3 serology be used instead of DNA sequencing where resources are limited. Samples giving indeterminate results by V3 peptide serology should be analyzed by direct DNA sequencing to distinguish between B-GPGR and the Brazilian variant B"-GWGR.


[Dissociation of the mast cell-lymphocyte rosettes].
It is established that incubation of the mast cells and lymphocytes in vitro in the medium 199 at 4 degrees C promotes spontaneous formationof mast cell-lymphocyte rosettes. While incubating in medium 199 at 37 degrees C a considerable part of mast cell-lymphocyte rosettes irreversibly dissociate in contrast to E-rosettes. Loss of ability to the formation of rosettes is due to the loss of the corresponding complementary structures mainly by the mast cells. The data are obtained which allow supposing participation in the process of dissociation of the shedding and capping phenomena induced by contact interaction of ++mast cells and lymphocytes.


Enhancement of arsenic trioxide cytotoxicity by dietary isothiocyanates in human leukemic cells via a reactive oxygen species-dependent mechanism.
Although clearly effective in acute promyelocytic leukemia (APL), arsenic trioxide (ATO) demonstrates little clinical benefit as a single agent in the treatment of non-APL hematological malignancies. We screened a library of 2000 marketed drugs and naturally occurring compounds to identify agents that potentiate the cytotoxic effects of ATO in leukemic cells. Here, we report the identification of three isothiocyanates (sulforaphane, erysolin and erucin) found in cruciferous vegetables as enhancers of ATO cytotoxicity. Both erysolin and sulforaphane significantly enhanced ATO-mediated cytotoxicity and apoptosis in a panel of leukemic cell lines; erucin activity was variable among cell types. Cellular exposure to sulforaphane in combination with ATO resulted in a dramatic increase in levels of reactive oxygen species (ROS) compared to treatment with either agent alone. Sulforaphane, alone or with ATO, decreased intracellular glutathione (GSH) content. Furthermore, addition of the free radical scavenger N-acetyl-l-cysteine (NAC) rescued cells from ATO/isothiocyanate-mediated cytotoxicity. Our data suggest that isothiocyanates enhance the cytotoxic effects of ATO through a ROS-dependent mechanism. Combinatorial treatment with isothiocyanates and ATO might provide a promising therapeutic approach for a variety of myeloid malignancies.


Perioperative Respiratory Adverse Events in Pediatric Ambulatory Anesthesia: Development and Validation of a Risk Prediction Tool.
Perioperative respiratory adverse events (PRAEs) are the most common cause of serious adverse events in children receiving anesthesia. Our primary aim of this study was to develop and validate a risk prediction tool for the occurrence of PRAE from the onset of anesthesia induction until discharge from the postanesthesia care unit in children younger than 18 years undergoing elective ambulatory anesthesia for surgery and radiology. The incidence of PRAE was studied. We analyzed data from 19,059 patients from our department's quality improvement database. The predictor variables were age, sex, ASA physical status, morbid obesity, preexisting pulmonary disorder, preexisting neurologic disorder, and location of ambulatory anesthesia (surgery or radiology). Composite PRAE was defined as the presence of any 1 of the following events: intraoperative bronchospasm, intraoperative laryngospasm, postoperative apnea, postoperative laryngospasm, postoperative bronchospasm, or postoperative prolonged oxygen requirement. Development and validation of the risk prediction tool for PRAE were performed using a split sampling technique to split the database into 2 independent cohorts based on the year when the patient received ambulatory anesthesia for surgery and radiology using logistic regression. A risk score was developed based on the regression coefficients from the validation tool. The performance of the risk prediction tool was assessed by using tests of discrimination and calibration. The overall incidence of composite PRAE was 2.8%. The derivation cohort included 8904 patients, and the validation cohort included 10,155 patients. The risk of PRAE was 3.9% in the development cohort and 1.8% in the validation cohort. Age ≤ 3 years (versus >3 years), ASA physical status II or III (versus ASA physical status I), morbid obesity, preexisting pulmonary disorder, and surgery (versus radiology) significantly predicted the occurrence of PRAE in a multivariable logistic regression model. A risk score in the range of 0 to 3 was assigned to each significant variable in the logistic regression model, and final score for all risk factors ranged from 0 to 11. A cutoff score of 4 was derived from a receiver operating characteristic curve to determine the high-risk category. The model C-statistic and the corresponding SE for the derivation and validation cohort was 0.64 ± 0.01 and 0.63 ± 0.02, respectively. Sensitivity and SE of the risk prediction tool to identify children at risk for PRAE was 77.6 ± 0.02 in the derivation cohort and 76.2 ± 0.03 in the validation cohort. The risk tool developed and validated from our study cohort identified 5 risk factors: age ≤ 3 years (versus >3 years), ASA physical status II and III (versus ASA physical status I), morbid obesity, preexisting pulmonary disorder, and surgery (versus radiology) for PRAE. This tool can be used to provide an individual risk score for each patient to predict the risk of PRAE in the preoperative period.


Appropriateness of Tympanostomy Tubes in the Boston Metropolitan Area: Are the AAO-HNSF Guidelines Being Met?
Introduction Otitis media (OM) is the most common reason children receive general anesthesia, with bilateral tympanostomy tube (TT) insertion the second most common surgery in children. Prior research suggests overuse of TT. As part of a project designed to improve appropriateness of OM referrals, we evaluated appropriateness of TT insertion in a patient cohort. Methods Patients younger than 9 years with initial otolaryngology (ORL) visits in academic and private office settings for OM from January 1, 2012, to August 31, 2013, were identified through claims database. A detailed retrospective chart review of patients undergoing TT insertion was performed to determine appropriateness of TT insertion per the 2013 American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) guidelines. Results A total of 120 patients undergoing TT insertion were randomly chosen for detailed chart review; 32 patients were excluded. Sixty-six (75%) of 88 patients available for analysis met AAO-HNSF guidelines for TT. Recurrent acute OM with middle ear effusion was the most common indication (56%). Other indications included chronic OME and TT in at-risk patients with speech, learning, or behavioral delays. Of the 22 patients undergoing TT insertion not meeting AAO-HNSF guidelines, 11(50%) had abnormal exams, but were 1 to 2 infections short of meeting guidelines; 7 (33%) had normal exams but met criteria for number of infections. Discussion Contrary to prior publications, 75% of patients undergoing TT insertion had an appropriate indication per AAO-HNSF guidelines. In only 5% was TT insertion a substantial departure from guidelines. Implications for Practice The study outcomes suggest appropriate clinical decision making, improved guideline adherence, and better guideline applicability from the previously published 1994 and 2004 guidelines.


Predictors of a Successful Urology Resident Using Medical Student Application Materials.
To evaluate features from the medical student application record that predict for a high-quality urology resident because there are currently sparse data on factors that are associated with a successful urology residency. We reviewed the Mayo Clinic experience with 53 urology residents who matriculated between 2000 and 2011. Residents were independently scored 1-10 based on overall quality by the Program Director and Associate Program Director. Discrepant scoring by >2 was resolved by the former Program Director. Associations of features from the medical student application with an excellent score (defined as 8-10) were evaluated with logistic regression. Discrepant scoring >2 was noted in only 3 residents (6%). Among the 53 residents, the mean overall score was 6.2 (standard deviation 3.0, range 1-10) and 20 residents (38%) had an excellent score of 8-10. Univariably, higher United States Medical Licensing Examination step II score (P = .011), election to Alpha Omega Alpha (P = .017), no negative interview comments (P = .044), lower ranked medical school (P = .015), honors in obstetrics and gynecology clerkship (P = .044), and honors in all core clinical clerkships (P = .007) were significantly associated with an excellent score. In a multivariable model, no negative interview comments (P = .018), lower ranked medical school (P = .012), and honors in all core clinical clerkships (P = .006) were independently associated with an excellent score; the c-index for this model was 0.91. We demonstrate features associated with an excellent urology resident, most notably an honors grade in all core clinical clerkships.


Chemoprevention of tumors: the role of RAR-beta.
Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The knowledge of carcinogenic mechanisms provides the scientific rationale for chemoprevention. Epithelial carcinogenesis proceeds through multiple discernible stages of molecular and cellular alterations. Understanding of the multistep nature of carcinogenesis has evolved through highly controlled animal carcinogenesis studies, and these studies have identified three distinct phases: initiation, promotion and progression. Animal model studies have provided evidence that the development of cancer involves many different factors, including alterations in the structures and functions of different genes. Transitions between successive stages can be enhanced or inhibited in the laboratory by different types of agents, such activities providing the fundamental basis for chemoprevention.


Performance of Al2O3:C optically stimulated luminescence dosimeters for clinical radiation therapy applications.
A commercial Optical Stimulated Luminescence (OSL) dosimetry system developed by Landauer was tested to analyse the possibility of using OSL dosimetry for external beam radiotherapy planning checks. Experiments were performed to determine signal sensitivity, dose response range, beam type/energy dependency, reproducibility and linearity. Optical annealing processes to test OSL material reusability were also studied. In each case the measurements were converted into absorbed dose. The experimental results show that OSL dosimetry provides a wide dose response range, good linearity and reproducibility for the doses up to 800cGy. The OSL output is linear with dose up to 600cGy range showing a maximum deviation from linearity of 2.0% for the doses above 600cGy. The standard deviation in response of 20 dosimeters was 3.0%. After optical annealing using incandescent light, the readout intensity decreased by approximately 98% in the first 30 minutes. The readout intensity, I, decreased after repeated optical annealing as a power law, given by I infinity t (-1.3). This study concludes that OSL dosimetry can provide an alternative dosimetry technique for use in in-vivo dosimetry if rigorous measurement protocols are established.


Cardiovascular risk in women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a heterogeneous disease affecting about 5-10% of reproductive-age female population, which is predominantly characterized by chronic anovulation, hyperandrogenism and insulin resistance. PCOS women represent an intriguing biological model illustrating the relationship between hormonal pattern and cardiovascular risk profile, presenting a cluster of cardiovascular features, such as obesity, insulin resistance, hypertension, impaired cardiopulmonary functional capacity, autonomic dysfunction and low-grade chronic inflammation. Metabolic syndrome should be also considered in the clinical evaluation and management of PCOS. The treatment of PCOS and its complications should not be based solely on pharmacological therapies trying to improve hyperandrogenism, hyperinsulinemia and insulin resistance. Although mounting evidence recognizes the beneficial effects of lifestyle modifications, the clinical management of PCOS is not sufficiently focused on long-term maintenance of both exercise and dietary interventions and on further aspects of this syndrome (i.e. psychological status). Taking into consideration the patients' young age and the devastating effects of PCOS on hormonal and metabolic pattern, this complex and multifaceted disease requires a comprehensive approach in order to achieve concrete beneficial effects for PCOS patients. Multidisciplinary programs, including dietary and educational counseling, exercise training, stress management and psychosocial support, might represent the gold standard for adequate reduction of cardiovascular risk in young women with PCOS.


Cryopreservation of artificial gut microbiota produced with in vitro fermentation technology.
Interest in faecal microbiota transplantation (FMT) has increased as therapy for intestinal diseases, but safety issues limit its widespread use. Intestinal fermentation technology (IFT) can produce controlled, diverse and metabolically active 'artificial' colonic microbiota as potential alternative to common FMT. However, suitable processing technology to store this artificial microbiota is lacking. In this study, we evaluated the impact of the two cryoprotectives, glycerol (15% v/v) and inulin (5% w/v) alone and in combination, in preserving short-chain fatty acid formation and recovery of major butyrate-producing bacteria in three artificial microbiota during cryopreservation for 3 months at -80°C. After 24 h anaerobic fermentation of the preserved microbiota, butyrate and propionate production were maintained when glycerol was used as cryoprotectant, while acetate and butyrate were formed more rapidly with glycerol in combination with inulin. Glycerol supported cryopreservation of the Roseburia spp./Eubacterium rectale group, while inulin improved the recovery of Faecalibacterium prausnitzii. Eubacterium hallii growth was affected minimally by cryopreservation. Our data indicate that butyrate producers, which are key organisms for gut health, can be well preserved with glycerol and inulin during frozen storage. This is of high importance if artificially produced colonic microbiota is considered for therapeutic purposes.


Cancer Drug Price and Novelty in Mechanism of Action.
Many economic theories point to regulatory issues and subsidization of research and development costs as the primary factor in the high cancer drug prices in the US. Even so, the association between the median annual cost and novelty of cancer drugs approved in the US remains unclear. To evaluate the association between the median annual cost and novelty of cancer drugs approved in the US over a 6-year period. This cross-sectional study included all cancer drugs approved by the US Food and Drug Administration (FDA) from January 1, 2015, to December 31, 2020. Drug names, indications, manufacturer, dosage, and measures of activity/efficacy were extracted from the FDA announcement. The search was performed in December 2021. Data were analyzed from January 2022 until April 2022. Annual cost of treatment was calculated based on average wholesale price collected from the 2021 Micromedex Red Book database. Mechanism of action was inferred from trial publication or its references. There were 224 cancer drug approvals across 119 individual drugs, with a median annual cost of $196 000 (IQR, $170 000-$277 000). Gene and viral therapies were the most expensive (median, $448 000 [IQR, $448 000-$479 000]), followed by small molecule therapy (median, $244 000 [IQR, $203 000-$321 000), and biologics (median, $185 000 [IQR, $148 000-$195 000]). There was no significant difference in cost between first-in-class, next-in-class, and subsequent approvals of an already approved drug. Findings of this study indicate that the median annual price of anticancer drugs in the US is not associated with the novelty of their mechanism of action.


Active Use and Engagement in an mHealth Initiative Among Young Men With Obesity: Mixed Methods Study.
The effectiveness of mobile health (mHealth) approaches that employ wearable technology to promote physical activity have been the subject of concern due to the declining active use observed in trial settings. To better contextualize active use, this study aimed to identify the barriers and enablers to engagement in a tracker-based mHealth initiative among young men who had recently completed a 19-week residential weight loss program. A mixed methods study was conducted among 167 young men who had voluntarily enrolled in the national steps challenge (NSC), an mHealth physical activity promotion initiative, following a residential weight loss intervention. A subsample of 29 enrollees with a body mass index of 29.6 (SD 3.1) participated in semistructured interviews and additional follow-up assessments. Quantitative systems data on daily step count rates were used to describe active use. Qualitative data were coded and analyzed to elicit barriers and enablers to microlevel engagement in relation to the NSC, focusing on tracker and smartphone use. We further elicited barriers and enablers to macrolevel engagement by exploring attitudes and behaviors toward the NSC. Using triangulation, we examined how qualitative engagement in the NSC could account for quantitative findings on active use. Using integration of findings, we discussed how the mHealth intervention might have changed physical activity behavior. Among the 167 original enrollees, active use declined from 72 (47%) in week 1 to 27 (17%) in week 21. Mean daily step counts peaked in week 1 at 10,576 steps per day and were variable throughout the NSC. Barriers to engagement had occurred in the form of technical issues leading to abandonment, device switching, and offline tracking. Passive attitudes toward step counting and disinterest in the rewards had also prevented deeper engagement. Enablers of engagement included self-monitoring and coaching features, while system targets and the implicit prospect of reward had fostered new physical activity behaviors. Our study showed that as the NSC is implemented in this population, more emphasis should be placed on technical support and personalized activity targets to promote lasting behavior change.


Food safety and pharmacokinetic studies which support a zero (0) meat and milk withdrawal time for use of sometribove in dairy cows.
Sometribove (SB) is a synthetic form of bovine somatotropin (BST) whose amino acid sequence is the same for 190 of the 191 amino acids in BST. Administration of 500 mg of SB to dairy cows every 14 d increases the efficiency of milk production. Regulatory agencies have authorized a zero (0) milk and meat withdrawal time for investigational use of SB. The scientific basis for this authorization is as follows: 1) BST and other non-primate somatotropins are not active in humans, due to differences in the amino acid sequence from human somatotropin, which limits the ability of BST to bind to receptors on human tissues. 2) SB is not orally active, as it is degraded like other proteins when eaten. Administration of 50,000 microgram/kg/d SB to rats for 90 d produced no growth response. 3) Residual levels of SB in meat/milk are very low (ppb) and comparable to endogenous BST levels. 4) Residual levels (ppb) of insulin-like growth factor I (IGF-I) in meat and milk are only marginally increased by SB treatment (somatotropin stimulates local production of IGF-I in tissues to mediate some of its biological effects. 5) IGF-I was not orally active when fed to rats at doses ranging from 200 to 2,000 microgram/kg for 14 d.


Developmentally regulated autophagy is required for eye formation in Drosophila.
The compound eye of the fruit fly Drosophila melanogaster is one of the most intensively studied and best understood model organs in the field of developmental genetics. Herein we demonstrate that autophagy, an evolutionarily conserved selfdegradation process of eukaryotic cells, is essential for eye development in this organism. Autophagic structures accumulate in a specific pattern in the developing eye disc, predominantly in the morphogenetic furrow (MF) and differentiation zone. Silencing of several autophagy genes (Atg) in the eye primordium severely affects the morphology of the adult eye through triggering ectopic cell death. In Atg mutant genetic backgrounds however genetic compensatory mechanisms largely rescue autophagic activity in, and thereby normal morphogenesis of, this organ. We also show that in the eye disc the expression of a key autophagy gene, Atg8a, is controlled in a complex manner by the anterior Hox paralog Lab (Labial), a master regulator of early development. Atg8a transcription is repressed in front of, while activated along, the MF by Lab. The amount of autophagic structures then remains elevated behind the moving MF. These results indicate that eye development in Drosophila depends on the cell death-suppressing and differentiating effects of the autophagic process. This novel, developmentally regulated function of autophagy in the morphogenesis of the compound eye may shed light on a more fundamental role for cellular self-digestion in differentiation and organ formation than previously thought. αTub84B, α-Tubulin at 84B; Act5C, Actin5C; AO, acridine orange; Atg, autophagy-related; Ato, Atonal; CASP3, caspase 3; Dcr-2; Dicer-2; Dfd, Deformed; DZ, differentiation zone; eGFP, enhanced green fluorescent protein; EM, electron microscopy; exd, extradenticle; ey, eyeless; FLP, flippase recombinase; FRT, FLP recognition target; Gal4, gene encoding the yeast transcription activator protein GAL4; GFP, green fluorescent protein; GMR, Glass multimer reporter; Hox, homeobox; hth, homothorax; lab, labial; L3F, L3 feeding larval stage; L3W, L3 wandering larval stage; lf, loss-of-function; MAP1LC3, microtubule-associated protein 1 light chain 3; MF, morphogenetic furrow; PE, phosphatidylethanolamine; PBS, phosphate-buffered saline; PI3K/PtdIns3K, class III phosphatidylinositol 3-kinase; PZ, proliferation zone; Ref(2)P, refractory to sigma P, RFP, red fluorescent protein; RNAi, RNA interference; RpL32, Ribosomal protein L32; RT-PCR, reverse transcription-coupled polymerase chain reaction; S.D., standard deviation; SQSTM1, Sequestosome-1, Tor, Target of rapamycin; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay; UAS, upstream activation sequence; qPCR, quantitative real-time polymerase chain reaction; w, white.


Distribution of arbuscular mycorrhizal fungi (AMF) in Terceira and São Miguel Islands (Azores).
The data, presented here, come from samples collected during three research projects which aimed to assess the impact of land-use type on Arbuscular Mycorrhizal Fungi (AMF) diversity and community composition in pastures of Terceira Island (Azores, Macaronesia, Portugal) and also in the native forest of two Azorean Islands (Terceira and São Miguel; Azores, Macaronesia, Portugal). Both projects contributed to improving the knowledge of AMF community structure at both local and regional scales. Little is known on the AMF communities from Azores islands and this study reports the first survey in two Azorean Islands (Terceira and São Miguel). A total of 18,733 glomeromycotan spores were classified at the species level from 244 field soil samples collected in three different habitat types - native forests (dominated by Juniperus brevifolia and Picconia azorica), semi-natural and intensively-managed pastures. Thirty-seven distinct spore morphotypes, representing ten glomeromycotan families, were detected. Species of the family Acaulosporaceae dominated the samples, with 13 species (38% of the taxa), followed by Glomeraceae (6 spp.), Diversisporaceae (4 spp.), Archaeosporaceae (3 spp.), Claroideoglomeraceae (3 spp.), Gigasporaceae (3 spp.), Ambisporaceae and Paraglomeraceae, both with the same number of AMF species (2 spp.), Sacculosporaceae (1 sp.) and Entrophospora (family insertae sedis). Members of the family Acaulosporaceae occurred almost exclusively in the native forests especially associated with the Picconia azorica rhizosphere, while members of Gigasporaceae family showed a high tendency to occupy the semi-natural pastures and the native forests of Picconia azorica. Members of Glomeraceae family were broadly distributed by all types of habitat which confirm the high ecological plasticity of this AMF family to occupy the more diverse habitats.


Transcallosal inhibition and motor conduction studies in patients with schizophrenia using transcranial magnetic stimulation.
Transcranial magnetic stimulation of the motor cortex may not only elicit excitatory responses in hand muscles contralateral to the stimulated hemisphere, but may also suppress tonic voluntary electromyogram activity in muscles ipsilateral to the stimulation. This inhibition is mediated between the motor cortices via the corpus callosum. To investigate motor excitability and interhemispheric (transcallosal) connections in patients with schizophrenia. Transcallosal inhibition and motor conduction parameters were investigated in ten patients with schizophrenia and in ten age- and gender-matched healthy subjects. Transcallosal conduction time (TCT) and duration of the inhibition were significantly longer in patients with schizophrenia (mean (s.d.)): TCT, 12.4 (2.9) ms in normal subjects and 15.3 (2.6) ms in patients (P = 0.03); mean duration, 34.1 (4.9) ms in normal subjects and 51.9 (16.8) ms in patients (P = 0.01). Magnetic motor conduction parameters are unaltered in schizophrenia, but transcallosal inhibition is significantly delayed and prolonged. This may indicate abnormal function of the corpus callosum in these patients.


Lanthanide and actinide doped B12H122- and Al12H122- clusters: new magnetic superatoms with f-block elements.
In recent years, actinide containing clusters have attracted immense attention because of the distinctive bonding properties of their 5f and 6d electrons. In this context, in the present work, we have studied the isoelectronic series of actinide (An = Np+, Pu2+, Am3+) doped B12H122- and Al12H122- clusters using density functional theory (DFT). Similarly, corresponding isoelectronic lanthanide (Ln = Pm+, Sm2+, Eu3+) doped clusters are also investigated using DFT for comparison. Both exohedral and endohedral metal doped Al12H122- clusters are investigated in various possible spin states, whereas for B12H122- only exohedral metal doped clusters are studied due to its smaller cage diameter. Among all the metal doped clusters, the exohedral metal doped B12H122- and Al12H122- clusters in a septet spin state with retained high spin population on the doped actinide ion, are the most stable, indicating that all these doped clusters are magnetic in nature. The high stability of exohedral clusters is due to small steric repulsion as compared to that in the corresponding endohedral clusters. A prominent charge transfer from cage to metal ion is responsible for the strong interaction of the doped metal ion with the cage atoms. The studied Ln@B12H122- (Ln@Al12H122-) and An@B12H122- (An@Al12H122-) clusters are not only thermodynamically stable, but also kinetically stable. Metal ion encapsulated endohedral Al12H122- clusters are found to satisfy the 32-electron principle corresponding to the completely filled s, p, d and f shells of the central f-block atom. Theoretical predictions of these lanthanide and actinide doped stable B12H122- and Al12H122- clusters could encourage experimentalists for the preparation of these metal-doped clusters. Thus, the present work offers borane and alane clusters as new hosts for encapsulating radioactive actinides. Furthermore, various functional derivatives of these actinide doped B12H122- clusters may find applications in the field of radiation medicine.


Looking forward and back: distress among women at familial risk for breast cancer.
Healthy women with family histories of breast cancer in a first-degree relative (FH+) have been reported to exhibit higher levels of breast cancer-related distress than women without family histories of breast cancer (FH-). Recent data suggest that this may be particularly true for women who had a parent die of cancer. In line with theories emphasizing the psychological impacts of past stressors and concerns for the future, the present study examined the hypotheses that past cancer stressors (i.e. maternal breast cancer caregiving and death, "Looking Back") and perceptions of one's own heightened future risk for developing the disease ("Looking Forward") would predict current levels of distress. One hundred forty-eight healthy women (57 FH+, 91 FH-) recruited from large medical centers in the New York City area completed measures of breast cancer-related distress, general psychological distress, and items assessing whether or not they had taken care of their mother with breast cancer or had had their mother die from the disease. Consistent with previous research, results indicated that FH+ women whose mothers had died of breast cancer had significantly higher breast cancer-related distress than either FH+ women whose mothers had not died of breast cancer or FH- women (p < .05). Further analyses revealed that FH+ women who had cared for their mothers with breast cancer had higher cancer-related distress than women who did not (p < .01), and that FH+ women whose experience included both caregiving and the death of their mother from breast cancer had the highest levels of cancer-related distress (p < .01) and depressive symptoms (p < .05). Findings also indicated that FH+ women with heightened perceptions of risk for breast cancer had higher levels of distress, independent of past stressors. These findings suggest that psychosocial interventions for women with family histories of breast cancer might be appropriately focused on these issues.


Emerging Detection Techniques for Large Vessel Occlusion Stroke: A Scoping Review.
Background: Large vessel occlusion (LVO) is the obstruction of large, proximal cerebral arteries and can account for up to 46% of acute ischaemic stroke (AIS) when both the A2 and P2 segments are included (from the anterior and posterior cerebral arteries). It is of paramount importance that LVO is promptly recognised to provide timely and effective acute stroke management. This review aims to scope recent literature to identify new emerging detection techniques for LVO. As a good comparator throughout this review, the commonly used National Institutes of Health Stroke Scale (NIHSS), at a cut-off of ≥11, has been reported to have a sensitivity of 86% and a specificity of 60% for LVO. Methods: Four electronic databases (Medline via OVID, CINAHL, Scopus, and Web of Science), and grey literature using OpenGrey, were systematically searched for published literature investigating developments in detection methods for LVO, reported from 2015 to 2021. The protocol for the search was published with the Open Science Framework (10.17605/OSF.IO/A98KN). Two independent researchers screened the titles, abstracts, and full texts of the articles, assessing their eligibility for inclusion. Results: The search identified 5,082 articles, in which 2,265 articles were screened to assess their eligibility. Sixty-two studies remained following full-text screening. LVO detection techniques were categorised into 5 groups: stroke scales (n = 30), imaging and physiological methods (n = 15), algorithmic and machine learning approaches (n = 9), physical symptoms (n = 5), and biomarkers (n = 3). Conclusions: This scoping review has explored literature on novel and advancements in pre-existing detection methods for LVO. The results of this review highlight LVO detection techniques, such as stroke scales and biomarkers, with good sensitivity and specificity performance, whilst also showing advancements to support existing LVO confirmatory methods, such as neuroimaging.


Development of a ReaxFF reactive force field for aqueous chloride and copper chloride.
Copper ions play crucial roles in many enzymatic and aqueous processes. A critical analysis of the fundamental properties of copper complexes is essential to understand their impact on a wide range of chemical interactions. However the study of copper complexes is complicated by the presence of strong polarization and charge transfer effects, multiple oxidation states, and quantum effects like Jahn-Teller distortions. These complications make the experimental observations difficult to interpret. In order to provide a computationally inexpensive yet reliable method for simulation of aqueous-phase copper chemistry, ReaxFF reactive force field parameters have been developed. The force field parameters have been trained against a large set of DFT-derived energies for condensed-phase copper-chloride clusters as well as chloride/water and copper-chloride/water clusters sampled from molecular dynamics (MD) simulations. The parameters were optimized by iteratively training them against configurations generated from ReaxFF MD simulations that are performed multiple times with improved sets of parameters. This cycle was repeated until the ReaxFF results were in accordance with the DFT-derived values. We have performed MD simulations on chloride/water and copper-chloride/water systems to validate the optimized force field. The structural properties of the chloride/water system are in accord with previous experimental and computational studies. The properties of copper-chloride/water agreed with the experimental observations including evidence of the Jahn-Teller distortion. The results of this study demonstrate the applicability of ReaxFF for the precise characterization of aqueous copper chloride. This force field provides a base for the design of a computationally inexpensive tool for the investigation of various properties and functions of metal ions in industrial, environmental, and biological environments.


Forecasting COVID-19 Case Trends Using SARIMA Models during the Third Wave of COVID-19 in Malaysia.
With many countries experiencing a resurgence in COVID-19 cases, it is important to forecast disease trends to enable effective planning and implementation of control measures. This study aims to develop Seasonal Autoregressive Integrated Moving Average (SARIMA) models using 593 data points and smoothened case and covariate time-series data to generate a 28-day forecast of COVID-19 case trends during the third wave in Malaysia. SARIMA models were developed using COVID-19 case data sourced from the Ministry of Health Malaysia's official website. Model training and validation was conducted from 22 January 2020 to 5 September 2021 using daily COVID-19 case data. The SARIMA model with the lowest root mean square error (RMSE), mean absolute percentage error (MAE) and Bayesian information criterion (BIC) was selected to generate forecasts from 6 September to 3 October 2021. The best SARIMA model with a RMSE = 73.374, MAE = 39.716 and BIC = 8.656 showed a downward trend of COVID-19 cases during the forecast period, wherein the observed daily cases were within the forecast range. The majority (89%) of the difference between the forecasted and observed values was well within a deviation range of 25%. Based on this work, we conclude that SARIMA models developed in this paper using 593 data points and smoothened data and sensitive covariates can generate accurate forecast of COVID-19 case trends.


[A method for determining specific circulating immune complexes in patients with acute Sonne dysentery].
The antigen-specific method for the determination of specific immune complexes in the blood serum of patients with acute Sonne dysentery has been developed on the basis of the enzyme-linked immunosorbent assay with the use of reagents manufactured in the USSR. The possibility of the early prognostication of prolonged carrier state by using the proposed method for the determination of the level of specific circulating immune complexes has been shown.


Melatonin receptors in the pituitary of a teleost fish: mRNA expression, 2-[(125)I]iodomelatonin binding and cyclic AMP response.
Melatonin has for a long time been involved in the photoperiodic control of fish physiology (growth, reproduction) and behavior (locomotor activity); but its mechanisms of action are not understood. We show here that 2-[(125)I]iodomelatonin binds specifically to membrane preparations from Pike (Esox lucius, L.) pituitaries (K(D): 556 pM; B(max): 2.8 fmol/mg proteins). Radioautography indicated that the binding was restricted to a part of the pituitary only. Using polymerase chain reaction from pike genomic DNA, we subcloned two partial cDNAs encoding the P1.4 (Mel(1a)) and the P2.6 (Mel(1b)) melatonin receptor subtypes. The two corresponding transcripts were expressed in the pituitary as revealed by RT-PCR assay and Southern blot hybridization. In culture, melatonin inhibited in a time- and dose-dependent manner cyclic AMP levels in pituitaries cultured in the presence of forskolin, an adenylyl cyclase activator. This is the first evidence for the expression of melatonin receptors and binding sites, and for the modulation of a second messenger by melatonin in the pituitary of a nonmammalian species. We suggest that in fish, the melatonin-mediated photoperiodic control of neuroendocrine functions involves, at least, a direct effect on the pituitary.


Audit of completion of radiology request form in a nigerian specialist hospital.
Clinical audit is one approach to improve the quality of patient care, completion of request form inclusive. Radiology request forms are essential communication tools between the clinician and the radiologist. The aim of this study is to audit the adequacy of completion of X-ray request forms. A review of all consecutive request form received at the X-ray unit of the over a period of six weeks to assess the completeness of filling of the forms, details of biodata/clinical information, previous exposure and information about the requesting officer. The data was entered into a SPSS statistical software and analysed descriptively and results presented in tables/figures. Two hundred and two request forms were analysed. All the request had names on it however 89.1% had complete and adequate information while 10.9% have incomplete and inadequate information on names, one hundred and ninety-six (97%) had dates while, 6(3%) did not have information regarding date of request, space for the addresses were filled in 80 (39.6%) out of which only 24 (11.9%) had adequate and complete information. Clinical information were adequate and complete in 34.4%, only 6(8.3%) of those with previous x-rays submitted their previous film with the new request. We concluded that radiological investigation forms are still incompletely and inadequately filled. This will have effect on the quality and the overall service provided by both the radiographer and the radiologist and may have effect sometimes on the clinical decision and outcome.


Lack of defined apheresis collection criteria in publicly available CAR-T cell clinical trial descriptions: Comprehensive review of over 600 studies.
Chimeric antigen receptor T (CAR-T) cell successes have encouraged continued clinical study. Apheresis collection of starting material for CAR-T cell therapy product manufacturing is critical but described approaches suggest variability and clinical guidelines are currently lacking. The goal of this study was to gather and assess variability in apheresis collection descriptions in publicly available CAR T-cell therapy clinical trials. We searched clinicaltrials.gov (a publicly available clinical trial database) for "chimeric antigen receptor T cells" on July 01, 2020 and studies accessed July 30, 2020-August 15, 2020. Data collected included date posted, study characteristics, apheresis mentions (number, location, and context), laboratory parameters and transfusion allowances. Apheresis context was analyzed using a qualitative inductive approach of grounded theory method with open coding. Text was classified into 37 context codes, grouped into 12 categories, and then consolidated into patient, procedure, product, and miscellaneous themes. Apheresis was mentioned 1044 times in 322 (51.9%) of 621 total studies. Laboratory parameters mentioned included white blood cells (100 studies), absolute neutrophil count (220 studies), absolute lymphocyte count (102 studies), CD3+ cell (38 studies), hemoglobin (233 studies, 54 studies specified transfusion allowance), and platelet (269 studies, 48 studies specified transfusion allowance). Apheresis collection of CAR-T cell products is not well-defined in clinical study descriptions and the context is inconsistent. Laboratory parameters useful for apheresis collection are variably present and do not consistently align with current practices. Further exploration, and clinical guideline development will encourage alignment of apheresis collections for CAR-T cell products.


Overexpression of U1 snRNA induces decrease of U1 spliceosome function associated with Alzheimer's disease.
We recently reported that presenilin-1 (PS1) induced an increase of U1 snRNA expression accompanied with the change of amyloid precursor protein expression, β-amyloid level and cell death. In the present study, our data showed that both overexpression and knockdown of U1 snRNA could cause the loss in the function of U1 snRNA and resulted in PCPA as well as the same downstream phenomena including the expression changes of genes specific to AD, tau hyperphosphorylation on the site of Thr212, the decrease of acetylated α-tubulin, the reduction of cell viability and upregulation of RIPK1, RIPK3 and caspase8. These findings not only helped researchers better understand the functions of U1 snRNA, but also paved the way to reveal the mechanisms of AD from a different point of view and may find a new therapeutic target for the disease.


Novel Approach for Isolation and Identification of Porcine Epidemic Diarrhea Virus (PEDV) Strain NJ Using Porcine Intestinal Epithelial Cells.
Porcine epidemic diarrhea virus (PEDV), which is the causative agent of porcine epidemic diarrhea in China and other countries, is responsible for serious economic losses in the pork industry. Inactivated PEDV vaccine plays a key role in controlling the prevalence of PEDV. However, consistently low viral titers are obtained during the propagation of PEDV in vitro; this represents a challenge to molecular analyses of the virus and vaccine development. In this study, we successfully isolated a PEDV isolate (strain NJ) from clinical samples collected during a recent outbreak of diarrhea in piglets in China, using porcine intestinal epithelial cells (IEC). We found that the isolate was better adapted to growth in IECs than in Vero cells, and the titer of the IEC cultures was 104.5 TCID50/0.1 mL at passage 45. Mutations in the S protein increased with the viral passage and the mutations tended towards attenuation. Viral challenge showed that the survival of IEC-adapted cultures was higher at the 45th passage than at the 5th passage. The use of IECs to isolate and propagate PEDV provides an effective approach for laboratory-based diagnosis of PEDV, as well as studies of the epidemiological characteristics and molecular biology of this virus.


Tailoring nanostructure and bioactivity of 3D-printable hydrogels with self-assemble peptides amphiphile (PA) for promoting bile duct formation.
3D-printing has expanded our ability to produce reproducible and more complex scaffold architectures for tissue engineering applications. In order to enhance the biological response within these 3D-printed scaffolds incorporating nanostructural features and/or specific biological signaling may be an effective means to optimize tissue regeneration. Peptides amphiphiles (PAs) are a versatile supramolecular biomaterial with tailorable nanostructural and biochemical features. PAs are widely used in tissue engineering applications such as angiogenesis, neurogenesis, and bone regeneration. Thus, the addition of PAs is a potential solution that can greatly expand the utility of 3D bioprinting hydrogels in the field of regenerative medicine. In this paper, we firstly developed a 3D-printable thiolated-gelatin bioink supplemented with PAs to tailor the bioactivity and nanostructure which allows for the incorporation of cells. The bioink can be printed at 4 °C and stabilized to last a long time (>1 month) in culture at 37 °C by via a dual secondary crosslinking strategy using calcium ions and homobifunctional maleiminde-poly (ethylene glycol). Rheological properties of inks were characterized and were suitable for printing multi-layered structures. We additionally demonstrated enhanced functionality of ink formulations by utilizing a laminin-mimetic IKVAV-based PA system within a 3D-printable ink containing cholangiocytes. Viability and functional staining showed that the IKVAV PA nanofibers stimulated cholangioctyes to form functional tubular structures, which was not observed in other ink formulations.


2019 ISCB Innovator Award recognizes William Stafford Noble.
The International Society for Computational Biology (ISCB) Innovator Award honors an ISCB scientist who is within two decades of having completed his or her graduate degree and has made outstanding contributions to the field of computational biology. The 2019 winner is Dr. William Stafford Noble, Professor in the Department of Genome Science, University of Washington. Noble will receive his award and deliver a keynote presentation at the 2019 Joint International Conference on Intelligent Systems for Molecular Biology/European Conference on Computational Biology in Basel, Switzerland being held on July 21-25, 2019.


Equivalent responses to lexical and nonlexical visual stimuli in occipital cortex: a functional magnetic resonance imaging study.
Stimulus-related changes in cerebral blood oxygenation were measured using high-resolution functional magnetic resonance imaging sequentially covering visual occipital areas in contiguous sections. During dynamic imaging, healthy subjects silently viewed pseudowords, single false fonts, or length-matched strings of the same false fonts. The paradigm consisted of a sixfold alternation of an activation and a control task. With pseudowords as activation vs single false fonts as control, responses were seen mainly in medial occipital cortex. These responses disappeared when pseudowords were alternated with false font strings as the control and reappeared when false font strings instead of pseudowords served as activation and were alternated with single false fonts. The string-length contrast alone, therefore, is sufficient to account for the activation pattern observed in medial visual cortex when word-like stimuli are contrasted with single characters.


Poor Long-Term Outcomes of Keratopigmentation With Black Ink for the Treatment of Dysphotopsia Secondary to Laser Peripheral Iridotomies.
To report outcomes of keratopigmentation (KP) with commercial black ink in the treatment of dysphotopsia secondary to laser peripheral iridotomies (LPI) using manual anterior stromal puncture (ASP) and manual lamellar pocket (LP). This is a retrospective case series of eyes that underwent KP for treatment of dysphotopsia secondary to LPI. Patients' postoperative symptoms were categorized as resolved, improved, no change, or worse. Any intraoperative and postoperative complications were noted, as well as the need for further treatments. Five eyes in 4 patients underwent ASP, and 14 eyes in 13 patients underwent LP. Only 1 patient had improvement in symptoms in the AK group. Four patients had a complete resolution of symptoms after LP, whereas 7 had symptomatic improvement and 3 did not notice any change. Fifty-five percent of patients in the LP group experienced late-onset depigmentation between 3 and 5 years postoperatively. One patient who underwent 2 LP re-treatments experienced irregular corneal steepening with nonprogressive corneal thinning. Overall, there were no serious adverse reactions to the pigment used. ASP was not suitable for the treatment of dysphotopsia secondary to LPI. In the short term, LP had good outcomes, but commercial black ink was prone to depigmentation at 3 to 5 years postoperatively. We therefore do not recommend the use of such pigment for long-term management of dysphotopsia secondary to LPI.


A left-ear advantage for forced-choice judgements of melodic contour.
Listeners heard a sequence of five tones presented monaurally, and then made a forced-choice judgement about the sequence's contour (i.e., its pattern of upward and downward shifts in pitch between successive tones). The forced-choice method ensured that contoured judgements were independent of absolute-pitch an interval cues. Performance was better for sequences presented to the left ear (right hemisphere) than it was for sequences presented to the right ear (left hemisphere). This finding provides support for claims of a right-hemisphere bias for the processing of melodic contour.


Langmuir and scatchard parameters do not describe the binding of Actinomyces viscosus to saliva-treated hydroxyapatite.
The binding of Actinomyces viscosus T14V to saliva-treated spheroidal hydroxyapatite (SHA) beads was studied. The association constant (K) and the total number of binding sites (N) obtained from the Langmuir plots were in good agreement with those reported by other workers (approx. 3 X 10(-8) and 3 X 10(8), respectively). The values for N obtained from Scatchard plots differed from those obtained from Langmuir plots by factors of 10(6) or more. These results suggest that either these equations are inappropriate to describe binding or certain assumptions regarding this system are not being met. The use of these models requires, among other constraints, that the process be reversible and that measurements be taken at equilibrium. A method was developed which allowed a close examination of the equilibrium dynamics without perturbation of the system. The results suggest that the adsorption process is only poorly reversible. Adsorption to SHA was not at equilibrium after 1.5 h. Even when bacteria were allowed to adsorb for longer periods, and the system appeared to approach equilibrium, the increased time of adherence did not significantly alter the derived K or N values. Our results suggest that the use of Scatchard and Langmuir plots is inappropriate to describe binding of A. viscosus to SHA.


Making a Killer: Selecting the Optimal Natural Killer Cells for Improved Immunotherapies.
Over the past 20 years natural killer (NK) cell-based immunotherapies have emerged as a safe and effective treatment option for patients with relapsed or refractory leukemia. Unlike T cell-based therapies, NK cells harbor an innate capacity to eliminate malignant cells without prior sensitization and can be adoptively transferred between individuals without the need for extensive HLA matching. A wide variety of therapeutic NK cell sources are currently being investigated clinically, including allogeneic donor-derived NK cells, stem cell-derived NK cells and NK cell lines. However, it is becoming increasingly clear that not all NK cells are endowed with the same antitumor potential. Despite advances in techniques to enhance NK cell cytotoxicity and persistence, the initial identification and utilization of highly functional NK cells remains essential to ensure the future success of adoptive NK cell therapies. Indeed, little consideration has been given to the identification and selection of donors who harbor NK cells with potent antitumor activity. In this regard, there is currently no standard donor selection criteria for adoptive NK cell therapy. Here, we review our current understanding of the factors which govern NK cell functional fate, and propose a paradigm shift away from traditional phenotypic characterization of NK cell subsets towards a functional profile based on molecular and metabolic characteristics. We also discuss previous selection models for NK cell-based immunotherapies and highlight important considerations for the selection of optimal NK cell donors for future adoptive cell therapies.


The impact that the influenza A (H1N1) pandemic had on news reporting in the state of Paraná, Brazil.
This study aims to analyze how influenza A (H1N1) in 2009 was reported in the state of Paraná. A total of 189 articles were analyzed in two newspapers from Paraná. Pursuant to analysis, four themes were identified: the spread of the virus; the pandemic and fear; influenza in the health service; and influenza in public policies. By studying how influenza A was reported in the media, it was possible to see the social impact that the H1N1 pandemic represented for society, presenting challenges for public institutions and ordinary citizens, who sensed that they were in a high-risk group exposed to a potentially lethal virus. This disease radically changed the habits of a globalized community seeking to escape from vulnerability.


Intraoperative monitoring for safety of total hip arthroplasty using third-generation cementing technique.
Controversies on the safety of the cement application between cemented and uncemented total hip arthroplasty (THA) have been existing for decades. The purpose of this study was to observe the changes in mean arterial pressure (MAP), heart rate (HR) and oxygen pressure (PaO(2)) during cemented THA, and to evaluate the intraoperative safety of using the third-generation cementing technique and investigate whether the intraoperative risk is higher in acute femoral neck fracture patients than non-traumatic patients. Forty-two patients who underwent cemented THA between November 2005 and September 2007 were prospectively included in this study. The third-generation cementing technique as vacuum mixing and pulsatile lavage was used strictly. The MAP and HR were monitored and documented during each operation. Blood gas analysis was performed at exposure, cup implantation, stem implantation and wound closure. MAP, HR and PaO(2) were compared between pre- and post-cement application. Comparisons of MAP, HR and PaO(2) between patients with acute femoral neck fracture and non-traumatic patients were performed as well. No intraoperative cardiopulmonary complication occurred in these cases. No obvious changes were observed in MAP, HR and PaO(2) after cement application. There was no significant difference in MAP, HR and PaO(2) between acute femoral fracture patients (18 patients) and non-traumatic patients (24 patients). The results of this study suggested that the invasive blood pressure monitoring and blood gas analysis are essential for patients undergoing cemented THA, especially for patients with femoral neck fracture. The third-generation cementing technique is safe to use in THA.


Antibody Production after COVID-19 Vaccination in Patients with Inborn Errors of Immunity.
Few studies have evaluated COVID-19 vaccine efficacy in patients with inborn errors of immunity (IEI). To evaluate the levels of antibody (Ab) production and function after COVID-19 vaccination in IEI patients with phagocytic, complement, and Ab deficiencies and their comparison with healthy controls. Serum samples were collected from 41 patients and 32 healthy controls at least one month after the second dose of vaccination, while clinical evaluations continued until the end of the third dose. Levels of specific anti-receptor-binding domain (RBD) IgG and anti-RBD neutralizing antibodies were measured using EUROIMMUN and ChemoBind kits, respectively. Conventional SARS-CoV-2 neutralization test (cVNT) was also performed. Cutoff values of ≤20, 20-80, and ≥80 (for cVNT and Chemobined) and 0.8-4.2, 4.2-8.5, and ≥8.5 (for EUROIMMUN) were defined as negative/weak, positive/moderate, and positive/significant, respectively. A considerable distinction was observed between the Ab-deficient patients and the controls for Ab concentration (EUROIMMUN, p<0.01) and neutralization (ChemoBind, p<0.001). However, there was no significant difference compared with the other patient groups. A near-zero cVNT in Ab-deficient patients was found compared to the controls (p<0.01). A significant correlation between the two kits was found using the whole data (R2=0.82, p<0.0001). Despite varying degrees of Ab production, all Ab deficient patients, as well as almost half of those with complement and phagocytic defects, did not effectively neutralize the virus (cVNT). In light of the decreased production and efficiency of the vaccine, a revised immunization plan may be needed in IEI.


Pesticide toxicity: a mechanistic approach.
Pesticides are known for their high persistence and pervasiveness in the environment, and along with products of their biotransformation, they may remain in and interact with the environment and living organisms in multiple ways, according to their nature and chemical structure, dose and targets. In this review, the classifications of pesticides based on their nature, use, physical state, pathophysiological effects, and sources are discussed. The effects of these xenobiotics on the environment, their biotransformation in terms of bioaccumulation are highlighted with special focus on the molecular mechanisms deciphered to date. Basing on targeted organisms, most pesticides are classified as herbicides, fungicides, and insecticides. Herbicides are known as growth regulators, seedling growth inhibitors, photosynthesis inhibitors, inhibitors of amino acid and lipid biosynthesis, cell membrane disrupters, and pigment biosynthesis inhibitors, whereas fungicides include inhibitors of ergosterol biosynthesis, protein biosynthesis, and mitochondrial respiration. Insecticides mainly affect nerves and muscle, growth and development, and energy production. Studying the impact of pesticides and other related chemicals is of great interest to animal and human health risk assessment processes since potentially everyone can be exposed to these compounds which may cause many diseases, including metabolic syndrome, malnutrition, atherosclerosis, inflammation, pathogen invasion, nerve injury, and susceptibility to infectious diseases. Future studies should be directed to investigate influence of long term effects of low pesticide doses and to minimize or eliminate influence of pesticides on non-target living organisms, produce more specific pesticides and using modern technologies to decrease contamination of food and other goods by pesticides.


Studies on the photolytic breakdown of hydroperoxides and peroxidized fatty acids by using electron spin resonance spectroscopy. Spin trapping of alkoxyl and peroxyl radicals in organic solvents.
Spin trapping using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) has been used to detect and distinguish between the carbon-centred, alkoxyl, and peroxyl radicals produced during the photolytic decomposition of hydroperoxides. Photolysis of tert-butyl and cumene hydroperoxides, and peroxidized fatty acids, in toluene, with low levels of u.v. light, is shown to lead to the initial production of alkoxyl radicals by homolysis of the oxygen-oxygen bond. Subsequent reaction of these radicals with excess hydroperoxide leads, by hydrogen abstraction, to the production of peroxyl radicals that can be detected as their corresponding adducts with the spin trap. Subsequent breakdown of these adducts produces alkoxyl radicals and a further species that is believed to be the oxidized spin-trap radical 5,5-dimethyl-1-pyrrolidone-2-oxyl. No evidence was obtained at low hydroperoxide concentrations, with either the cumene or lipid alkoxyl radicals, for the occurrence of beta-scission reactions; the production of low levels of carbon-centred radicals is believed to be due to the alternative reactions of hydrogen abstraction, ring closure, and/or 1,2 hydrogen shifts. Analogous experiments with 3,3,5,5-tetramethyl-1-pyrroline N-oxide (TMPO) led only to the trapping of alkoxyl radicals with no evidence for peroxyl radical adducts, this is presumably due to a decreased rate of radical addition because of increased steric hindrance.


Anti-Inflammatory Ergosteroid Derivatives from the Coral-Associated Fungi Penicillium oxalicum HL-44.
To obtain the optimal fermentation condition for more abundant secondary metabolites, Potato Dextrose Agar (PDA) medium was chosen for the scale-up fermentation of the fungus Penicillium oxalicum HL-44 associated with the soft coral Sinularia gaweli. The EtOAc extract of the fungi HL-44 was subjected to repeated column chromatography (CC) on silica gel and Sephadex LH-20 and semipreparative RP-HPLC to afford a new ergostane-type sterol ester (1) together with fifteen derivatives (2-16). Their structures were determined with spectroscopic analyses and comparisons with reported data. The anti-inflammatory activity of the tested isolates was assessed by evaluating the expression of pro-inflammatory factors Tnfα and Ifnb1 in Raw264.7 cells stimulated with LPS or DMXAA. Compounds 2, 9, and 14 exhibited significant inhibition of Ifnb1 expression, while compounds 2, 4, and 5 showed strong inhibition of Tnfα expression in LPS-stimulated cells. In DMXAA-stimulated cells, compounds 1, 5, and 7 effectively suppressed Ifnb1 expression, whereas compounds 7, 8, and 11 demonstrated the most potent inhibition of Tnfα expression. These findings suggest that the tested compounds may exert their anti-inflammatory effects by modulating the cGAS-STING pathway. This study provides valuable insight into the chemical diversity of ergosteroid derivatives and their potential as anti-inflammatory agents.


Transport of ellipsoid fibers in oscillatory shear flows: Implications for aerosol deposition in deep airways.
It is widely acknowledged that inhaled fibers, e.g. air pollutants and anthropogenic particulate matter, hold the ability to deposit deep into the lungs reaching the distal pulmonary acinar airways as a result of their aerodynamic properties; these particles tend to align with the flow and thus stay longer airborne relative to their spherical counterpart, due to higher drag forces that resist sedimentation. Together with a high surface-to-volume ratio, such characteristics may render non-spherical particles, and fibers in particular, potentially attractive airborne carriers for drug delivery. Until present, however, our understanding of the dynamics of inhaled aerosols in the distal regions of the lungs has been mostly limited to spherical particles. In an effort to unravel the fate of non-spherical aerosols in the pulmonary depths, we explore through numerical simulations the kinematics of ellipsoid-shaped fibers in a toy model of a straight pipe as a first step towards understanding particle dynamics in more intricate acinar geometries. Transient translational and rotational motions of micron-sized ellipsoid particles are simulated as a function of aspect ratio (AR) for laminar oscillatory shear flows mimicking various inhalation maneuvers under the influence of aerodynamic (i.e. drag and lift) and gravitational forces. We quantify transport and deposition metrics for such fibers, including residence time and penetration depth, compared with spherical particles of equivalent mass. Our findings underscore how deposition depth is largely independent of AR under oscillatory conditions, in contrast with previous works where AR was found to influence deposition depth under steady inspiratory flow. Overall, our efforts underline the importance of modeling oscillatory breathing when predicting fiber deposition in the distal lungs, as they are inhaled and exhaled during a full inspiratory cycle. Such physical insight helps further explore the potential of fiber particles as attractive carriers for deep airway targeting.


Unsuccessful attempts to collect ova by surgical fixation of uterine catheters in superovulated cows.
Attempts were made to collect ova from superovulated cows by surgically fixing indwelling silastic balloon catheters in the uterine lumen. No ova were collected from the four catheterised cows and it was shown that ovarian activity was depressed. In this group, only 16 ovulations occurred compared with six control cows in which a total of 121 ovulations were recorded and 84 ova were collected. Also the ovaries of the catheterised cows had six large cysts, whereas no cysts were recorded in the control cows. The catheters flushed perfectly and bacteriological cultures of the flushing and uteri showed that no infections had occurred. The cows tolerated the catheters extremely well. There was no depression in appetite nor was any abnormal behaviour recorded. However, the severe depression of ovulation and the formation of ovarian cystic follicles prevents the technique from having any practical application as a means of collecting ova.


Chemical synthesis of proteins.
Proteins have become accessible targets for chemical synthesis. The basic strategy is to use native chemical ligation, Staudinger ligation, or other orthogonal chemical reactions to couple synthetic peptides. The ligation reactions are compatible with a variety of solvents and proceed in solution or on a solid support. Chemical synthesis enables a level of control on protein composition that greatly exceeds that attainable with ribosome-mediated biosynthesis. Accordingly, the chemical synthesis of proteins is providing previously unattainable insight into the structure and function of proteins.


Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds.
At present, wound treatment of inherited epidermolysis bullosa (EB) is only supportive. To determine the safety and clinical effects of tissue-engineered skin (Apligraf; Organogenesis Inc, Canton, Mass) in the healing of wounds of patients with different types of EB. An open-label uncontrolled study of 15 patients with EB treated with tissue-engineered skin. Each patient received tissue-engineered skin on up to 2 wounds on each of 3 clinic visits: day 1, week 6, and week 12. They were evaluated 7 (+/- 3) days and 6 weeks after each round of treatment. A quality-of-life survey was administered during week 6. University of Miami, Miami, Fla. Volunteers with EB. Safety and wound healing. A total of 69 different acute wounds received tissue-engineered skin at the day-1 (24 wounds), week-6 (23 wounds), and week-12 (22 wounds) visits. Overall, 63 wounds (79%) were found healed at the day-7 visit. Of the acute wounds, 82% (51/62) were healed 6 weeks after being treated, 75% (27/36) after 12 weeks, and 79% (11/14) after 18 weeks. Nine chronic wounds were also treated. Four were healed at 6 weeks; however, 7 were still open at the last clinic visit (week 18). There were no signs of rejection or clinical infection and no adverse events related to the tissue-engineered skin. The quality of life for most patients improved after treatment. Compared with patients' recollection of wounds treated with standard dressings, healing was faster and less painful. In this series of patients, tissue-engineered skin induced very rapid healing, was not clinically rejected, and was devoid of adverse effects. It was felt by the patients and families to be more effective than conventional dressings for EB wounds.


Levels of sex steroid hormones and their receptors in women with preeclampsia.
Pregnant women have high serum concentrations of sex steroid hormones, which are major regulators of paracrine and autocrine responses for many maternal and placental functions. The main purpose of this study was to compare patients with preeclampsia and patients with uncomplicated pregnancies in terms of serum steroid hormones (estradiol [E2], progesterone [P4], dehydroepiandrosterone sulfate [DHEAS], and testosterone [T]) throughout pregnancy and the levels of cord blood and placental steroid receptors during the third trimester. Quantitative real-time reverse transcription PCR, western blotting, and immunohistochemistry were used to determine the levels of steroid hormones in the serum and cord blood and the placental levels of estrogen receptor-α (ERα), ERβ, androgen receptor (AR), and progesterone receptor (PR). There were 45 women in the uncomplicated pregnancy group and 30 women in the preeclampsia group. Serum levels of T were greater and serum levels of E2 were reduced in the preeclampsia group, but the two groups had similar levels of P4 and DHEAS during the third trimester. Cord blood had a decreased level of DHEAS in the preeclampsia group, but the two groups had similar levels of P4, E2, and T. The two groups had similar placental mRNA levels of ERα, ERβ, AR, and PR, but the preeclampsia group had a higher level of ERβ protein and a lower level of ERα protein. Immunohistochemistry indicated that the preeclampsia group had a greater level of ERβ in the nucleus and cytoplasm of syncytiotrophoblasts and stromal cells. Women with preeclampsia had lower levels of steroid hormones, estrogen, and ERα but higher levels of T and ERβ. These molecules may have roles in the pathogenesis of preeclampsia.


Paper-PEG-based membranes for hydrophobic interaction chromatography: purification of monoclonal antibody.
This article discusses the preparation of novel Paper-PEG interpenetrating polymer network-based membranes as inexpensive alternative to currently available adsorptive membranes. The Paper-PEG membranes were developed for carrying out hydrophobic interaction membrane chromatography (HIMC). PEG is normally very hydrophilic but can undergo phase separation and become hydrophobic in the presence of high antichaotropic salt concentrations. Two variants of the Paper-PEG membranes, Paper-PEG 1 and Paper-PEG 2 were prepared by grafting different amounts of the polymer on filter paper and these were tested for their hydraulic properties and antibody binding capacity. The better of the two membranes (Paper-PEG 1) was then used for purifying the monoclonal antibody hIgG1-CD4 from simulated mammalian cell culture supernatant. The processing conditions required for purification were systematically optimized. The dynamic antibody binding capacity of the Paper-PEG 1 membrane was about 9 mg/mL of bed volume. A single step membrane chromatographic process using Paper-PEG 1 membrane gave high monoclonal antibody purity and recovery. The hydraulic permeability of the paper-based membrane was high and was maintained even after many runs, indicating that membrane fouling was negligible and the membrane was largely incompressible.


Metastatic chordoma of the tongue: Case report.
Chordomas are rare bone tumors that arise from notochord remnants. They most commonly occur in the sacrum, but they also can be seen in the skull base, cervical spine, and thoracolumbar vertebrae. Chordomas account for 1 to 4% of all primary skeletal tumors. They are usually indolent, locally growing tumors. Distant metastasis has been reported in 3 to 48% of cases. When metastasis occurs, it is usually observed in the lung, bone, and liver. To the best of our knowledge, no case of a chordoma metastasis to the tongue has been previously reported in the literature. We report such a case in a 61-year-old man.


The importance of remnant native vegetation of Amazonian submontane forest for the conservation of lizards.
Forest fragmentation affects animal population dynamics mainly by loss of habitat and disruption of animal movement. Lizard assemblages are affected by environmental changes, but, depending on their ecological needs, some species might be more vulnerable than others. The southern Amazon suffers accelerated anthropic actions replacing natural environments by farmland (crops and pasture). This region is considerably drier than most of the northern Amazon, with stational semi-deciduous forests fragmented and isolated by pasture, and crops to a lesser extent. Here we report data on lizard assemblages using semi-deciduous forests, forest edge and the surrounding pasture in the southern Amazon in Mato Grosso, Brazil. Lizards were collected in 21 forest fragments (41 to 7,035 ha) surrounded by pasture; using pitfall traps placed on a degradation gradient - from pasture inwards forest fragment (up to 200 m). We collected 242 individuals (14 species, seven families) in 6,300 trap-days. The pattern of species occurrence was largely nested and this nesting was associated with three habitat guilds (generalist, edge-tolerant, and forest species). Although there was no obvious fragmentation effect on lizards diversity community-wise, Hoplocercus spinosus, Bachia dorbignyi, Micrablepharus maximiliani and Kentropyx calcarta were more vulnerable to such effects than all other ten species collected. We verified that assemblages inhabiting pasture and forest edge are a nested subset of assemblages from the forest core. The remnant native vegetation is not distributed homogeneously and lizards species can persist in different parts of the landscape, therefore we recommend the protection of forest remnants as an important conservation action for lizards of the southern Amazon.


Relationship Between Subclinical Cardiovascular Diseases and Cardiac Morpho-Functional Parameters in Preclinical Stage A/B Heart Failure Adults with Type 2 Diabetes.
Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular disease which increases the risk of heart failure. This study aimed to determine whether clinical characteristics and subclinical cardiovascular disease (CVD) features are correlated with echocardiographic morpho-functional parameters of T2DM patients. Two hundred and fifty-five T2DM patients without a history of coronary heart disease were enrolled in this cross-sectional study. The demographic characteristics, glucose and lipid levels were assessed for each patient. Carotid ultrasonography and peripheral artery examination were performed to measure carotid intima-media thickness (cIMT), carotid plaque, ankle-brachial index (ABI), brachial artery pulse wave velocity (baPWV), and carotid-femoral pulse wave velocity (cfPWV). Furthermore, echocardiography was conducted to evaluate cardiac morphology and systolic and diastolic function. The relationship between clinical characteristics, subclinical cardiovascular diseases, and cardiac morpho-functional parameters was explored with the Pearson and stepwise multivariable linear regression analyses. A total of 255 subjects aged 18-80 years were enrolled in the study. Multiple regression analysis revealed that left ventricular mass index (LVMI) was correlated with age (β=0.463, p = 0.000) and systolic blood pressure (SBP) (β=0.179, p = 0.003). Relative wall thickness (RWT) was related to cfPWV (β=0.006, p = 0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (β=0.000, p = 0.036). In contrast, left ventricular ejection fraction (LVEF) was inversely related to cIMT (β=-0.925, p = 0.019). The ratio of the peak flow velocity of early diastole to atrial contraction (peak E/A) was correlated with age (β=-0.014, p = 0.000), diastolic blood pressure (DBP) (β=-0.006, p = 0.001) and cfPWV (β=-0.025, p = 0.044). In preclinical stage A/B heart failure adults with T2DM, age, BP, HOMA-IR, cfPWV and cIMT are correlated with cardiac morpho-functional parameters.


Particle clearance and histopathology in lungs of C3H/HeJ mice administered beryllium/copper alloy by intratracheal instillation.
Beryllium/copper (BeCu) alloys are commonly used in the electronics, automotive, consumer, defense, and aerospace industries. Some individuals exposed occupationally to BeCu alloys have developed chronic beryllium disease. However, little is known of the toxicity and fate of BeCu alloys in the respiratory tract. To begin to address this question, we investigated the pulmonary toxicity and clearance of BeCu alloy (2% Be; 98% Cu) in mice. Groups of 40 female C3H/HeJ mice were administered 12.5, 25, and 100 microg BeCu alloy or 2 and 8 microg Be metal by intratracheal instillation. Mice were sacrificed at 1 h and 1, 7, 14, and 28 days postinstillation. Left lungs were evaluated for histopathological change. Right lungs were analyzed for Be and Cu content. Twenty-five percent of the high-dose BeCu mice and 7.5% of the mid-dose BeCu mice died within 24 h of dosing. Acute pulmonary lesions included acute alveolitis and interstitial inflammation. Type II epithelial cell hyperplasia and centriacinar fibrosis were present by 7 days after dosing. Lesions persisted through 28 days after instillation. No lesions attributable to alloy exposure were present in liver or kidney. Be metal instillation caused no deaths and minimal pulmonary changes over the time studied, indicating that the pulmonary lesions were due to Cu rather than Be. Cu cleared the lung with a half-time of 0. 5-2 days. Be cleared with a half-time of several weeks or longer. Results of this study suggest that exposure to BeCu alloy is more acutely toxic to lung than Be metal. The results of tissue analyses also indicate that, while the Cu component of the alloy clears the lung rapidly, Be is retained and may accumulate upon repeated exposure.


Analysis of Internal Dermatology Matches Following the COVID-19 Pandemic.
Dermatology has long been recognized as a highly competitive field within medicine, with extremely limited spots available for aspiring dermatologists to secure residencies across the United States. We sought to evaluate the trends and factors influencing the match process in dermatology residencies, particularly given the changes brought on by the COVID-19 pandemic. Using data from publicly available match lists and regional categorizations, we studied the rates of internal and regional matches for dermatology applicants in the postpandemic era (2022-2023) compared with prepandemic statistics. Overall, the research sheds light on the evolving dynamics of dermatology residency matching in response to pandemic-induced changes and applicant preferences.


High incidence of enterotoxin D producing Staphylococcus spp. in Brazilian cow's raw milk and its relation with coagulase and thermonuclease enzymes.
In this study, the enterotoxigenic potential of Staphylococcus strains (n = 574) isolated from raw milk samples (n = 140) was determined for their capacity to produce staphylococcal enterotoxins. In addition, the relationship between the presence of enterotoxins, coagulase, and thermonuclease (Tnase) was assessed. The results showed that 19% of Staphylococcus was enterotoxigenic, being able to produce at least one of the staphylococcal enterotoxins (A, B, C, and D). Most of the strains were able to produce enterotoxin D (68.8%), whereas 12.8% of the Staphylococcus strains were able to produce staphylococcal enterotoxin A. Besides, the production of more than one type of enterotoxins by the same strain was observed. Tnase was considered the best marker for enterotoxigenic potential of isolates, although some of them were negative for coagulase and Tnase but positive for enterotoxin production. Therefore, either the use of Tnase to assess Staphylococcus enterotoxigenic potential or the use of simple and easy screening tests for enterotoxin production should receive more attention when evaluating the pathogenic potential of foodborne Staphylococcus strains. Due to the association of both coagulase positive Staphylococcus and coagulase negative Staphylococcus with foodborne disease outbreaks, regulators and industries should pay more attention to enterotoxigenic Staphylococcus rather than focusing only on S. aureus or coagulase positive Staphylococcus. Finally, data found here suggest a high risk of staphylococcal intoxication with the consumption of raw milk or dairy products made from raw milk.


Inhibition of Oncogenic Transcription Factor REL by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines.
Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-κB subunits REL (human c-Rel) and p65 as compared to NF-κB p50, and inhibition of REL and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by REL in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis correlated with levels of cellular and nuclear REL. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a REL target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101-induced apoptosis, and overexpression of a transforming mutant of REL decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-κB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-κB DNA binding. Direct inhibitors of REL may be useful for treating B-cell lymphomas in which REL is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-related responses in normal cells.


HU binding to a DNA four-way junction probed by Förster resonance energy transfer.
The Escherichia coli protein HU is a non-sequence-specific DNA-binding protein that interacts with DNA primarily through electrostatic interactions. In addition to nonspecific binding to linear DNA, HU has been shown to bind with nanomolar affinity to discontinuous DNA substrates, such as repair and recombination intermediates. This work specifically examines the HU-four-way junction (4WJ) interaction using fluorescence spectroscopic methods. The conformation of the junction in the presence of different counterions was investigated by Förster resonance energy transfer (FRET) measurements, which revealed an ion-type conformational dependence, where Na(+) yields the most stacked conformation followed by K(+) and Mg(2+). HU binding induces a greater degree of stacking in the Na(+)-stabilized and Mg(2+)-stabilized junctions but not the K(+)-stabilized junction, which is attributed to differences in the size of the ionic radii and potential differences in ion binding sites. Interestingly, junction conformation modulates binding affinity, where HU exhibits the lowest affinity for the Mg(2+)-stabilized form (24 μM(-1)), which is the least stacked conformation. Protein binding to a mixed population of open and stacked forms of the junction leads to nearly complete formation of a protein-stabilized stacked-X junction. These results strongly support a model in which HU binds to and stabilizes the stacked-X conformation.


Isotonitazene: Fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland.
The paper describes the first three deaths reported in Europe involved in isotonitazene consumption, a potent benzimidazole derivate opioid consumed in the recreational drug scene. Isotonitazene powder and purity determination was performed on the sample collected in the first death scene by NMR, HRMS, GC-FTIR, ATR-FTIR and GC-MS. Isotonitazene purity was determined by GC-MS analysis and proton NMR, and was defined to be above 95 % and 98 %, respectively. Quantification of isotonitazene in biological samples was performed using a targeted analysis based on SPE extraction and ultra-high performance liquid chromatography tandem mass spectrometry. The isotonitazene median concentration in femoral whole blood was 1.20ng/mL. Isotonitazene concentration in hair was similar or even lower compared to that seen in fentanyl abusers. Isotonitazene distribution in tissues converges in the brain, lungs and heart, respectively. Surprisingly, isotonitazene concentration in liver is the lowest measured for all tissues and fluids analyzed. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of all three deaths was an acute intoxication with isotonitazene. Since isotonitazene toxic concentration levels are very low, the consumption of this new psychoactive drug is a real hazard for human health.


Responsibility, thought-action fusion, and thought suppression in Turkish patients with obsessive-compulsive disorder.
Although an inflated sense of responsibility, thought-action fusion, and thought suppression are influential factors in cognitive models of obsessive-compulsive disorder (OCD), their impact on OCD has generally been demonstrated in samples from Western countries. The aim of the present study is to evaluate these cognitive factors in Turkish patients with OCD, other anxiety disorders, and community controls. Group comparisons showed that responsibility based on self-dangerousness and thought suppression significantly distinguished OCD patients from patients with other anxiety disorders and controls. Moreover, correlation and discriminant function analyses indicated that thought-action fusion in morality and likelihood was also associated with OCD symptoms. The present findings provide support for the international validity and specificity of cognitive factors and model for OCD.